Pharmaceutical compositions and uses of oxazinoisoquinoline derivatives



United States Patent Oflice 3,551,565 PHARMACEUTICAL COMPOSITIONS ANDUSES OF OXAZINOISOQUINOLINE DERIVATIVES Frank H. Clarke, Jr., Armonk,N.Y., assignor to Geigy Chemical Corporation, Ardsley, N .Y., acorporation of New York No Drawing. Application Apr. 26, 1968, Ser. No.724,622, now Patent No. 3,470,171, dated Sept. 30, 1969, which is acontinuation-in-part of application Ser. No. 634,856, May 1, 1967.Divided and this application Feb. 18, 1969, Ser. No. 825,467

Int. Cl. A61k 27/00 US. Cl. 424-248 21 Claims ABSTRACT OF THE DISCLOSURE3-carboxamido, and substituted carboxamido, derivatives of9,10-dialkoXy-, 9,10,11-trialkoxy-, and 9,10- methylenedioxy1,3,4,6,7,11b hexahydro [1,4]oxazino [3,4a1isoquinolines, and theirsalts, possess tranquilizing and muscle relaxant properties. They can beprepared through treatment of derivatives of the corresponding 3-carboxylic acid with an amine. Typical embodiments are 3-car'boxamido9,10 dimethoxy 1,5,4,6,7,11b-hexahydro [1,4]oxazino[3,4a]isoquinolineand 3 (N,N-diethylcarboxamido)-9,10-dimethoxy 1,3,4,6,7,11b hexahydro-[1,4] oxazino [3,4a] isoquinoline.

CROSS REFERENCE This is a division of Ser. No. 724,622, filed Apr. 26,1968, now US. Pat. No. 3,470,171, which in turn is acontinuation-in-part of copending application Ser. No. 634,856, filedMay 1, 1967, now abandoned.

DETAILED DESCRIPTION The present invention pertains to novel derivativesof [1,4]oxazino[3,4]isoquinolines, to methods for their I preparationand use, and to intermediates useful in their preparation.

In particular, the present invention pertains to processes for thepreparation of compounds, and to the compounds themselves, of theformula:

By the term (lower) alkyl and derivations thereof utilizing the rootalk, such as (lower alkoxy, (lower) alkanoyloxy, and the like isintended unless otherwise qualified, a group comprising a branched orstraight hydrocarbon chain containing from one to six carbon atoms.Representative of (lower)alkyl groups are thus methyl,

3,551,565 Patented Dec. 29, 1970 ethyl, propyl, i-proply, butyl,s-butyl, t-butyl, pentyl, ispentyl, hexyl and the like. Embraced bylower alkoxy are groups containing from one to six carbon atoms andjoined through an oxygen ether bond, such as methoxy, ethoxy, i-propoxy,butoxy and the like. It is to be understood that When the nature of anyparticular functional group in these moieties requires two carbon atoms,the hydrocarbon portion of the moiety will have from two to seven carbonatoms. Thus (lower)alkanoyloxy is typified by acetoxy, propanoyloxy,butanoyloxy, pentanoyloxy, hexanoyloxy and the like.

With greater particularity to Formula I, the compounds of the presentinvention are named in accordance with the conventions of ChemicalAbstracts as derivatives of [1,4]- oxaziono[3,4a]isoquinoline, thenucleus of which is represented and numbered as follows:

The novel compounds of the present invention are thus derivatives of1,3,4,6,11=b hexahydro [1,4] oxazino- [3,4a] isoquinolines.

The compounds of the present invention are either unsubstituted orsubstituted by a (lower)alkoxy group, pre ferably methoxy, in the 11position and substituted by (lower)alkoxy groups, preferably methoxy, inthe 9 and 10 positions. Alternatively when unsubstituted in the 11position, there can be a methylenedioxy group bridging the 9 and 10positions. Preferred species are those which are disubstituted bymethoxy in the 9 and 10 positions.

A carboxamido group is in the 3-position of the compounds of the presentinvention. The amido group may be unsubstituted [R and R hydrogen],monosubstituted by a (lower)alkyl group [R =hydrogen, R (lower)alkyl,disubstituted by (lower)alkyl (R =(lower)alkyl, R (lower alkyl] ordisubstituted by a cyclic structure so that, together with the nitrogenatom, a heterocyclic group such as morpholino, piperazino, piperidino,pyrrolidino or the like is present.

The 3 carboxamido-1,3,4,6,7,l1b-hexahydro [1,4]-oxazino[3,4a]isoquinolines of the present invention, namely those ofFormula 1, possess tranquilizing and muscle re laxing properties. Theyare accordingly useful in combatting agitation and hyperactivity inanimals, in preoperat-ive treatment and in the treatment of anxiety,tension and apprehension occurring alone or in association with variousphysiological disorders. These compounds advantageously have a hightherapeutic index and do not appear to deplete norepinephine at normaldosage levels. Generally the compounds are administered at levels offrom about 5 to about mg./kg. of body weight although as with any agentof this type, the dose will vary depending upon the patient andcondition.

The tranquilizing and muscle relaxant properties of these compounds canbe conveniently observed in a variety of standard tests which arecorrelated pharmacologically with specific therapeutic responses. Forexample, tranquilizing action is observed in the Mouse Reflex Test inwhich for these compounds the ratios of the dose required to eifectprehensile reflex blocking to the dose required to effect tractionblocking are greater than 3. In the chloralose anesthetized cat withspinal column severed at the first cervical vertebra, depression of thepolysynaptic reflexes (linguo-mandibular and flexor) upon electricstimulation is observed for at least four hours at a dose of mg./kg.i.v., a pattern characteristic of a central muscle relaxant. A typicalneuroleptic response is observed in the Sidman Avoicance Test ingerbils. In the wild red fox, the compounds are qualitatively similar tochlordiazepoxide. In the monkey they cause reduced activity and friendlybehavior without ataxia.

These compounds can be administered parenterally or orally, preferablythe latter, in any of the usual pharmaceutical forms including tablets,capsules, powders, suspensions, solutions, syrups and the like,including sustained release preparations which may be compounded by anyof the known procedures. The compounds of the present invention areincorporated in compositions suitable for oral administration in solidand liquid unit dosage forms, standard modes of administration beingemployed. The term unit dosage form as used in this specification andclaims refers to physically discrete units suitable as unitary dosagesfor animals, each unit containing a predetermined quantity of activematerial calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical diluent, carrier orvehicle.

Powders are prepared by comminuting a compound of this invention to asuitably fine size and mixing with a similarly comminuted diluent. Thediluent can be an edible carbohydrate material such as starch. Asweetening agent or sugar may also be present as well as flavoring oil.

Capsules are made by preparing a powder mixture as described above andfilling formed gelatin sheaths. As an adjuvant to the filling operation,a lubricant such as talc, magnesium stearate and calcium stearate may beadded to the powder mixture before the filling operation.

Tablets are made by preparing a powder mixture, granulating or slugging,adding a lubricant and pressing into tablets. The powder mixture isprepared by mixing the compound, suitably comminuted, with a diluent orbase such as starch, sucrose, kaolin, dicalcium phosphate and the like.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste or acacia mucilage and forcing through a screen. Asan alternative to granulating, the powder mixture can be slugged, i.e.,run through the tablet machine and the resulting imperfectly formedtablets broken into pieces (slugs). The slugs can be lubricated toprevent sticking to the tablet forming dies by means of the addition ofstearic acid, a stearate salt, talc or mineral oil. The lubricatingmixture is then compressed into tablets. A protective coating consistingof a sealing coat of shellac, a coating of sugar and methylcellulose,and a polish coating of carnauba wax may be provided. Dyestuffs can beadded to these coatings to distinguish different unit dosages.

For parenteral administration, fluid unit dosage forms can be preparedby suspending or dissolving a measured amount of the compound in anon-toxic liquid vehicle suitable for injection.

One important embodiment of the present invention is the acid additionsalts of the compounds of Formula I which are derived frompharmaceutically acceptable nontoxic acids. Such pharmaceuticallyacceptable non-toxic salts include those derived from both organic andinorganic acids such as, without limitation, hydrochloric, hydrobromic,sulfuric, phosphoric, methanesulfonic, acetic, lactic, succinic, malic,maleic, aconitis, phthalic, tartaric, embonic and like acids.

The presence of asymmetric substitution on the 3- and llb-carbon atomspermits the existence of four isomeric forms. These correspond to thetwo enantiomorphs of the stereoisomer wherein the hydrogen atoms inpositions 3 and 11b are in the cis relationships and the twoenantiomorphs of the stereoisomer wherein these hydrogen atoms are inthe trans relationship. Two such stereoisomeric racemates have beenobtained and arbitrarily designated isomer I and isomer II, it beingbelieved on the basis of present studies that isomer I corresponds tocis and isomer 1I corresponds to trans. Isomer I can be 4 rearranged tothe more stable isomer II through the action of strong base. The twopairs of enantiomorphs, i.e. the mixture of racemic isomer I and racemicisomer II, are separable into the individual racemates throughfractional crystallization, chromatography or the like by reason oftheir different physical properties while the individual enantiomorphsof each pair are separated through the use of optically active acidsaccording to conventional techniques. All such isomeric forms are withinthe purview of the present invention.

The oxazinoisoquinoline derivatives utilized in the pres ent inventioncan be prepared in accordance with the procedures described in US. Pat.No. 3,370,171, the disclosure of which is hereby incorporated byreference.

The following examples will serve to further typify the nature of thepresent invention but should not be construed as a limitation on thescope thereof.

EXAMPLE 1 Typical of the compounds of the present invention, thesynthesis of which is described in US. Pat. No. 3,470,171, are3-(N,N-diethyl carboxamido) 9,10 dimethoxy 1,3,4,6,7,11bhexahydro[1,4]oxazino[3,4,a]isoquinoline, 3 (N,N diethylcarboxamido)9,10 methylenedioxy 1,3,4,6,11b hexahydro[1,4]oxazino[3,4a]isoquinoline, 3-(N,N-diethylcarboxamido) 9,10,11trimethoxy-1,3,4, 6,7,11b hexahydro [1,4]oxazino[3,4a]isoquinolinc, 3carboxamido 9,10 dimethoxy 1,3,4,6,7,1 lb hexahydro [1,4]oxazino[3,4a]isoquinoline, 3 carboxamido 9,10,11 trimethoxy 1,3,4,6,7,11bhexahydro[l,4] oxazino [3,4a]isoquinoline, 3 carboxamido 9,10methylenedioxy 1,3,4,6,7,11b-hexahydro [1,4]oxazino [3,4a]isoquinoline,3 (N ethylcarboxamido) 9,10 dimethoxy l,3,4,6,7,11b hexahydro[l,4]oxazino [3,4a]isoquinoline, 3 piperidinocarbonyl 9,10 dimethoxy1,3,4,6,7,11b hexahydro [1,4]oxazino[3,4a] isoquinoline, 3morpholinocarbonyl 9,10 dimethoxy 1,3,4,6,7,llb hexahydro[1,4]oxazino[3,4a]isoquinoline, 3 pyrrolidinocarbonyl 9,10 dimethoxy1,3,4,6, 7,11b-hexahydro [1,4]oxazino[3,4a]isoquinoline, 3-(N'-methylpiperazinocarbonyl) 9,10 dimethoxy 1,3,4,6,7, 11b hexahydro[1,4]oxazino[3,4a]isoquinoline, 3-[N- (2 hydroxyethyl)piperazinocarbonyl] 9,10 dimethoxy 1,3,4,6,7,11b hexahydro [1,4] oxazino[3,4a] isoquinoline, MP. and 3 piperazinocarbonyl 9,10 dimethoxy1,3,4,6,7,11 bhexahydro [1,4]oxazino [3.4a] isoquinoline.

EXAMPLE 2 A solution of 6.95 g. of 3-(N,N-diethylcarboxamido)- 9,10dimethoxy 1,3,4,6,7,11b hexahydro [1,41oxazino[3,4a]-isoquinoline in hotmethanol is treated with 2.4 g. of maleic acid dissolved in the samesolvent. Concentration and cooling causes precipitation of the maleatesalt which is collected by filtration.

Other salts such as the tartrate, succinate, citrate and the like areprepared in a similar manner.

EXAMPLE 3 Optical resolution of racemic 3-(N,N-diethylcarboxamido) 9,10dimethoxy 1,3,4,6,7,1lb hexahydro- [1,4]-oxazino 3,4a]isoquinoline Asolution of 11.55 g. of racemic 3'-(N,N-diethylcarboxamido)9,l0dimethoxy 1,3,4,6,7,11b hexahydro- [1,4]oxazino[3,4a]isoquinoline, M.P.121124 C., and 4.443 g. of ()-malic acid in 50 ml. of isopropanol isprepared by heating the components together. This solution is allowed tostand at room temperature for 18 hours after which time the crystals arecollected by filtration, washed with a little cold isopropanol and driedin vacuo at 40 C. The material so obtained is recrystallized fromisopropanol to yield the ()-malate of the (-)-base as colorless prisms,M.P. 9l-96 C., [011 -=59.8 (c.=2.03 in methanol). The base regeneratedfrom the mother liquors is enriched in the dextro-isomer.

The ()-malate of the ()-base is dissolved in 75 ml. of methylenechloride and shaken with 50 ml. of aqueous sodium carbonate. The organiclayer is separated and the aqueous layer is extracted twice with ml.portions of methylene chloride. The combined organic extracts are driedover magnesium sulfate, filtered and evaporated in vacuo at 100 C. toyield colorless crystals, which on further recrystallization fromisopropanol yields the free base,(-)-3-(N,N-diethylcarboxamido)-9',10-dimethoxy l,3,4,6,7,11bhexahydro-[l,4]0xazino[3,4a] isoquinoline (isomer II), M.P. l33l35 C.,=90.3 (c.=l.68 in methanol).

In an an analogous manner, there is obtained from (+)-malic acid and theracemic base or the partially resolved base which is enriched in isomer,the malate of (+)-3-(N,N-diethylcarboxamido) 9,10 dimethoxy1,3,4,6,7,l1b hexahydro-[1,4]oxazino[3,4a] isoquinoline, double M.P. 87,9196 C., [a] =+58.6. (c.=2.()9 in methanol). The corresponding freebase, (+)-3-(N,N-diethylcarboxamido) 9,10 dimethoxy- 1,3,4,6,7,11bhexahydro [1,4]oxazino[3,4a]isoquinoline (isomer II), aftercrystallization from isopropanol, demonstrates a melting point of1325-1334 C., =+90.8 (c. =1.98 in methanol).

EXAMPLE 4 Quantity/ Ingredient: capsule, mg.

3-N,N-diethylcarboxamido -9, Iii-dimethoxy- 1,3,4,6,7,1lb-hexahydro-[1,4]oxazino[3,4a] isoquinoline 100 Corn starch U.S.P. 200

The foregoing ingredients are mixed and introduced into a two-piece No.1 hard gelatin capsule. Pharmaceutically acceptable salts of the activeingredient, such as the hydrochloride, may alternatively be employed.

EXAMPLE 5 Quantity/ Ingredient: tablet, mg.

3- (N,N-diethylcarboxamido -9, l O-dimethoxy- 1,3,4,6,7, 11b-hexahydro-[ 1,4] oxazino 3,4a]

isoquinoline Corn starch U.S.P. 130

Lactose 160 Cab-O-Sil M-S colloidal silica 4 Gelatin U.S.P. 5 Magnesiumstearate U.S.P 1

[ 1C ON 0 wherein:

each of R and R taken independently is hydrogen or (lower)alkyl or R andR taken together with the nitrogen atom to which they are attached aremorpholino, piperidino, pyrrolidino, piperazino,N'-[(lower)alkyl]piperazino, N [hydroxy(lower)alky1]piperazino, or N-lower) alkoxy (lower) alkyl] pipcrazino; R is hydrogen or (lower)alkoxy;and each of R and R taken independently is (lower) alkoxy or R and Rtkane together when R is hydrogen, are methylenedioxy; and apharmaceutically acceptable acid addition salt thereof.

2. A composition according to claim 1 wherein said compound each of Rand R is hydrogen or (lower) alkyl of from 1 to 3 carbon atoms or R andR taken together with the nitrogen atom to which they are attached arepiperidino, morpholino, pyrrolidino, piperazino, N'- methylpiperazino orN-(Z-hydroxyethyl)piperazino; R is hydrogen or methoxy; and each of Rand R taken independently is methoxy or taken together when R ishydrogen are methylenedioxy.

3. A composition according to claim 2 where in said compound R and R is(lower)alkyl of from 1 to 3 carbon atoms.

4. A composition according to claim 1 where said compound is 3-(N,Ndiethylcarboxamido)-9,10 dimethoxy 1,3,4,7,11b hexahydro[l,4]oxazino[3,4a]isoquinoline, or a pharmaceutically acceptable acidaddition salt thereof.

5. A composition according to claim 1 where said compound is 3-piperidinocarbonyl-9,10-dimethoxy-l,3,4,6,7, 11b hexahydro[l,4]oxazino[3,4a]isoquinoline, or a pharmaceutically acceptable acidaddition salt thereof.

6. A composition according to claim 1 where said compound is3-morpholinocarbonyl-9,IO-dimethoxy-1,3,4,6,7, 11b hexahydro[1,4]oxazino[3,4a]isoquinoline, or a pharmaceutically acceptable acidaddition salt thereof.

7. A composition according to claim 1 where said compound is3-pyrrolidinocarbonyl-9-,l0-dimethoxy-l,3,4,6,7, 11b hexahydro[1,4]oxazino[3,4a1isoquinoline, or a pharmaceutically acceptable acidaddition salt thereof.

8. A composition according to claim 1 where said compound is3-(N-methylpiperazinocarbonyl)-9,l0-dimethoxy 1,3,4,6,7,11b hexahydro[1,4]oxazino[3,4a]isoquinoline, or a pharmaceutically acceptable acidaddition salt thereof.

9. A composition according to claim 1 where said compound is3-(N-ethylcarboxamido)-9,10-dimethoxy-1,3,4,6, 7,1 lb hexahydro[1,4]oxazino[3,4a]isoquinoline, or a pharmaceutically acceptable acidaddition salt thereof.

10. A composition according to claim 1 where said compound is3-piperazinocarbonyl-9,10-dimethoxy-1,3,4,6, 7,11b hexahydro [1,4]oxazino[3,4a]isoquinoline, or a pharmaceutically acceptable acidaddition salt thereof.

11. A composition according to claim 1 where said compound is3-[N'-(2-hydroxyetryl)piperazinocarbonyl]- 9,10 dimethoxy1,3,4,6,7,1lb-hexahydro [1,4]oxazino[3,4a]isoquinoline, or apharmaceutically acceptable acid addition salt thereof.

12. A composition according to claim 1 where said compound is3-(N,N-diethylcarboxamido) 9,10-methylenedioxy 1,3,4,1,1lbhexahydro[l,4]oxazino[3,4]isoquinoline, or a pharmaceutically acceptableacid addition salt thereof.

13. A composition according to claim 1 where said compound is 3 (N,Ndiethylcarboxamido)-9,10,1 l-trimethoxy1,3,4,6,7,11b-hexahydro-[1,4]oxazino[3,4a]isoquinoline, or apharmaceutically acceptable acid addition salt thereof.

14. A composition according to claim 1 where said compound is 3carboxamido 9,10 dimethoxy-l,3,4,6,7, 11b hexahydro[1,4]oxazino[3,4a]isoquinoline, or a pharmaceutically acceptable acidaddition salt thereof.

15. A composition according to claim 1 where said compound is3-carboxamido-9,10,1l-trimethoxy-1,3,4,6,7, 11b hexahydro[1,4]oxazino[3,4a]isoquinoline, or a pharmaceutically acceptable acidaddition salt thereof.

16. A composition according to claim 1 where said compound is3-carboxamido-9,IO-mcthylenedioxy-1,3,4,6,

7,11b hexahydro [1,4]oxazino[3,4a]isoquinoline, or a pharmaceuticallyacceptable acid addition salt thereof.

17. A composition according to claim 1 where said compound is trans3-(N,N-diethylcarboxamido)-9,10-dimethoxy 1,3,4,6,7,11b hexahydro[l,4]oxazino[3,4a] isoquinoline, or a pharmaceutically acceptable acidaddition salt thereof.

18. A composition according to claim 17 where said compound is thehydrochloride salt.

19. The method of effecting transquilization in an animal whichcomprises administering thereto a tranquilizing amount of a compound ofthe formula:

wherein:

piperazino, or N [(lower)alkoxy(lower)alkylJpiperazino; R is hydrogen or(lower)alkoxy; and each of R and R taken independently is (lower)alkoxyor R and R taken together when R is hydrogen, are methylenedioxy; or apharmaceutically acceptable acid addition salt thereof. 20. The methodaccording to claim 19 wherein from 5 to mg./kg. of body weight of trans3-(N,N-diethylcarboxamido) 9,10 dimethyl 1,3,4,6,7,11b-hexahydro-[1,4]oxazino[3,4a]isoquinoline or a pharmaceutically acceptable acidaddition salt thereof is administered.

21. The method according to claim 20 wherein said salt is thehydrochloride.

References Cited UNITED STATES PATENTS 2,286,390 6/1942 Sparks 260-2682,906,777 9/1959 Denss et a1 260-557 2,948,754 8/1960 Litvan et al.260-247.7 3,051,710 8/1962 Biel 260268 3,052,680 9/1962 Dupuy et al.260247.7 3,244,701 4/1966 Jiirgens et al. 260268 3,246,975 4/ 1966Hopkins 260247.

STANLEY J. FRIEDMAN, Primary Examiner U.S. Cl. X.R. 424-258 "14050UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3'55l'565 Dated ecem er 29, 1970 Inventor) Frank H. Clarke Jr.

It is certified that errorappears in the above-identified patent: andthat said Letters Patent are hereby corrected as shown below:

r- In Column 6:

Claim 4, line 22, instead of "l,3,4,7,llb" should appear l 3,4 6 7 llbClaim 11, line 51, "2-hydroxyetryl" should be 2-hydroxyethyl Claim 12,line 57 should appear as l,3,4,6,7,llbhexahydro[1,4]oxazino[3,4a]iso- InColumn 7:

Claim 19, line 10, "transquilization should be tranquilization Signedand sealed this 13th day of April 1971 (SEAL) Attest:

WILLIAM E. SGHUILER, JR. EDWARD MJLETGHERJR. Commissioner of PatentsAttesting Officer

